Toxicology of Industrial Compounds

H.M.BOLT 303
colorants based on carcinogenic congeners of benzidine (e.g. 3,3′dimethoxybenzidine;
3,3′-dimethylbenzidine) are most likely still being
manufactured in some countries. The case of pigments based on 3,3′dichlorobenzidine
is discussed below.
Azo colorants are biologically active through their metabolites.
Azoreduction of these compounds occurs in vivo (Radomski and
Mellinger, 1962; Rinde and Troll, 1975; Robens et al., 1980) by an
enzyme-mediated reaction. Azoreductases are found in mammalian tissues,
particularly in liver (Fouts et al., 1957; Walker, 1970; Martin and Kennelly,
1981; Kennelly et al., 1982) and also in gut bacteria (Yoshida and
Miyakawa, 1973; Chung et al., 1978; Hartmann et al., 1978; Cerniglia et
al., 1982; Bos et al., 1986). The result of this azoreduction is the release of
the (carcinogenic) aromatic amine from the colorant (Martin and Kennelly,
1985). Studies performed on exposed workers have demonstrated that the
azoreduction of benzidine-based colorants occurs in man (Genin, 1977;
Boeninger, 1978; Lowry et al., 1980; Meal et al., 1981; Dewan et al.,
1988). Studies of Lynn et al., (1980) and Bowman et al. (1983) have
demonstrated that the metabolic conversion of benzidine-, 3,3′dimethylbenzidine-
and 3,3′-dimethoxybenzidine-based colorants to their
(carcinogenic) amine precursors in vivo is a general phenomenon that must
be expected for each member of this class of chemicals.
However, in contrast to water-soluble dyes, the question of biological
azoreduction of (practically insoluble) pigments was a matter of discussion
in the recent years. One study has claimed the presence of 3,3'dichlorobenzidine
in the urine both of experimental animals fed with
Pigment Yellow 12 and of exposed workers (Akiyama, 1970). However,
other experimental studies, using more modern analytical tools, did not
confirm these results (DHEW, 1978; Leuschner, 1978; Mondino et al.,
1978; Nony et al., 1980).
Several epidemiological studies have demonstrated that the use of the
benzidine-based dyes has caused bladder cancer in humans. In a Japanese
study, the risk of bladder cancer among dye applicators (kimono painters)
was 6.8 times the expected rate (Yoshida et al., 1971). In a British study,
workers performing the dyeing of textiles (and not exposed to benzidine
itself) had a higher risk of bladder cancer (RR=3.4) than expected
(Anthony, 1974). In a USSR study, an increased incidence of bladder
cancer was found in workers who dried or ground benzidine-based dyes
(Genin, 1977).
In our own study on bladder cancer in painters (Myslak et al., 1991), the
time of first exposure (painters with bladder tumors) dated mostly back to
the first half of the century. Two factors may have been relevant: (1) at
that time, a large number of benzidine-based azodyes was in manufacture,
especially in Germany; (2) during that time it was usual for painters in
Germany to prepare their paints themselves. This work included grinding